Brose Discusses Lenvatinib's Lasting Impact in Treatment of Thyroid Cancer

Marcia S. Brose, MD, PhD

Patients with progressive radioactive iodine (RAI)-refractory differentiated thyroid cancer treated with lenvatinib (Lenvima) were found to have a significant duration of overall response (DOR), according to updated findings of the SELECT trial presented at the 2016 ASCO Annual Meeting.¹

The new efficacy data show that at cut-off, the median progression-free survival (PFS) was 19.4 months for lenvatinib (95% CI, 14.8-29.3) and 3.7 months (95% CI, 3.5-5.4) for placebo (HR, 0.24; 99% CI, 0.17-0.35; P <.0001).

In the 157 patients who received lenvatinib, the median DOR was 30 months (95% CI 18.4-35.2). This was similar across subgroups, except in patients with greater disease burden and those with liver metastases.

Earlier findings of the phase III trial showed that treatment with the multikinase inhibitor reduced the risk of disease progression by 79% (HR, 0.21; 99% CI, 0.14-0.31; P <.001). These results led to the FDA approval of lenvatinib for this indication in February 2015, creating another option for patients alongside the tyrosine kinase inhibitor sorafenib (Nexavar) for the first- or second-line setting.

Nevertheless, the 2 therapies have proven to be fairly comparable—and encouraging&mdash;in their results.

“Patients really have 2 options and, because of this, they are probably living longer based on the overall survival data in the 65-and-older group, and they are getting a benefit longer than they ever have before,” says Marcia S. Brose, MD, PhD. “The thyroid cancer patients who are getting diagnosed now are doing much better than the patients who are RAI-refractory even 10 years ago. Every option that we develop is basically another plus for patients.”

OncLive: How do you find that practitioners are using lenvatinib in comparison with sorafenib?

In an interview with OncLive, Brose, an associate professor of Otorhinolaryngology, Head and Neck Surgery, at the Hospital of the University of Pennsylvania, discusses the updated SELECT findings, how practitioners are treating patients with lenvatinib, how its use compares with sorafenib, and the challenges that still exist with both therapies for patients with thyroid cancer.Brose: It is interesting how much both are being used. I find that people are giving the agent that they feel most comfortable with first. There are some people who have a lot of experience with sorafenib and are going ahead and using it as their first-line choice, also because it was FDA approved first. There are other people who like the data on lenvatinib and are using that as their first line.

At the end of the day, most patients are getting both. The only difference is, really, which one that practitioners give first. Many of these patients, when they start to fail one therapy, are more than healthy and are able to go on to a second-line agent.

What is the optimal sequencing strategy with lenvatinib and sorafenib?

The bottom line for lenvatinib—since it has become approved&mdash;is that it is being used, probably, for all patients. Everyone is getting both lenvatinib and sorafenib.The correct answer for that is that we don’t have an answer, because we don’t have a sequencing study. There were enough differences in the population of the SELECT trial, where the patients were clearly more aggressive. It is impossible to compare the data because it is not apples to apples.

The answer I always give to people is, “It doesn’t matter because everyone is going to get both.” There are reasons why people pick one or the other first—issues that would bias people to choose one over the other is comfort and comorbidity. For instance, lenvatinib has a big issue with hypertension, and people with a lot of cardiac problems who are already on 3 medications are probably not going to get started on that.

For sorafenib, some people may be in manual labor and do a lot of stuff with their hands and feet, and they may choose that they do not want to start with sorafenib. Some patients may need a rapid response, and they may feel that the response with lenvatinib might be a little quicker, so they might start with that. At the end of the day, all patients are getting both. We don’t have an answer to optimal sequencing.

The problem is, patients who are getting sorafenib after lenvatinib may not do as well because the patients who were on the SELECT study initially were already very aggressive. Therefore, some people anecdotally might say, “I don’t give sorafenib after lenvatinib because the patients don’t do well.”

Will a sequencing study be conducted?

We really have no reliable data, and even our anecdotes aren’t reliable because of the way the trials rolled out. The optimal sequencing remains to be determined.I tried, and there is no interest whatsoever by either company to do it. The number of patients you would have to enroll is somewhere between 300 and 700 and, in a rare cancer, that’s just not going to happen.

What are the treatment challenges with using lenvatinib for these patients?

At the end of the day, both companies know that all patients will get exposed to both drugs. It would be nice to do it, and we might figure out a way to do it some time as a registration study, but right now it is not going to happen. We are not going to have that information anytime soon.The biggest treatment challenges with lenvatinib involve the kidney effects and hypertension. It is very important that doctors giving lenvatinib are very aware that hypertension is a problem, and that patients should be rapidly monitored. They should make sure they are reading their blood pressure correctly before they go home, and they should have patients visit at least 1 week in to make sure that their blood pressure is under control and that they are adequately medicated. That is the most hair-raising of the few treatment challenges with lenvatinib.

Weight loss is also a very big one. It is important that we try to recommend that people do muscle-strengthening exercises, because that tends to decrease the amount of weight loss and muscle loss that happens when they’re on the kinase inhibitors. We do that actually with both drugs.

What factors do you consider in choosing one therapy versus another in first-line?

With sorafenib, treatment challenges primarily remain to be the hand-foot skin reaction.It really goes along with the patient. If somebody is very symptomatic and needs to shrink a lesion very quickly, I might choose lenvatinib first. If they need more stability, I might take sorafenib first because there are data that lenvatinib works well in the second-line setting. We have data that lenvatinib works after sorafenib; we just don’t know how that compares to sorafenib after lenvatinib.

Updated findings from the SELECT trial were presented at the 2016 ASCO Annual Meeting. Can you provide some insight?

If patients don’t need a rapid response, I might give them sorafenib first, help them manage the hand-foot skin reaction upfront, and then give them lenvatinib in second-line. They are probably just as many patients for whom I would recommend lenvatinib first in situations, as I would with sorafenib first. Then, you have to choose it accordingly to the patient in front of you. You have to personalize it based on comorbidities, medical issues, or even desires about what kind of side effects are more manageable for that patient.This was a follow-up time point from the SELECT trial. The cut-off PFS was 19.4 months, so it is even a little bit better for lenvatinib. In telling us what we often thought throughout is obviously that patients who have a tumor shrinkage of 30% or greater often maintain the response for longer; it’s a good prognostic line.

The median DOR to lenvatinib was similar among subgroups. It is what I would expect. People with a greater disease burden didn’t last as long but generally patients who had at least a 30% response had a very good duration of that response.

Lenvatinib was also explored in a phase II study of patients with differentiated, medullary, and anaplastic thyroid cancer. What findings were reported here?

What do these findings suggest about lenvatinib going forward?

One of the other things about the SELECT trial is that it turns out that the overall survival (OS) of patients who were over 65 years was clearly improved. When you start talking about who you’re using it in, that would argue that if you have an OS benefit for the patients over 65, that is important. It was a big finding, because we have never shown an OS benefit in any of these trials, but also because of that data it makes people more willing to use this drug in an over-65 population.This was a phase II Japanese study (NCT01728623), and it just shows that it looks like there is some activity in anaplastic and medullary thyroid cancer. The PFS was 9.2 months, and that’s pretty good. It is not robust—it’s not as good as in the RAI-refractory group&mdash;but it is not bad. In the anaplastic group, the OS is around 1 year; and the PFS was around 7.4 months. There is a study going on, that will move forward for the anaplastic group.It is going to play a big role, and there might even be a role in medullary thyroid cancer, but the bottom line is it’s a very active agent. It has a role in thyroid cancer in probably all of the settings. It is interesting to see whether or not there might be other settings it might be involved in, but anaplastic is up right now.

1. Gianoukakis AG, Mathias EG, Dutcus C, et al. Response to lenvatinib treatment in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC): Updated results from SELECT. J Clin Oncol. 2016;34 (suppl; abstr 6089).